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      In Silico Molecular Modeling and Docking Analysis in Lung Cancer Cell Proteins

       Manisha Sritharan1 and Asita Elengoe2*

       1Department of Science and Biotechnology, Faculty of Engineering and Life Sciences, University of Selangor, Bestari Jaya, Selangor, Malaysia

       2Department of Biotechnology, Faculty of Science, Lincoln University College, Petaling Jaya, Selangor, Malaysia

       Abstract

      In this study, the three-dimensional (3D) models of lung cancer cell line proteins [epidermal growth factor (EGFR), K-ras oncogene protein, and tumor suppressor (TP53)] were generated and their binding affinities with curcumin, ellagic acid, and quercetin through local docking were assessed. Firstly, Swiss model was used to build lung cancer cell line proteins and then visualized by the PyMol software. Next, ExPASy ProtParam Proteomics server was used to evaluate the physical and chemical parameters of the protein structures. Furthermore, the protein models were validated using PROCHECK, ProQ, ERRAT, and Verify3D programs. Lastly, the protein models were docked with curcumin, ellagic acid, and quercetin by using BSP-Slim server. All three protein models were adequate and in exceptional standard. The curcumin showed binding energy with EGFR, K-ras oncogene protein, and TP53 at 5.320, 2.730, and 1.633, kcal/mol, respectively. Besides that, the ellagic acid showed binding energy of EGFR, K-ras oncogene protein, and TP53 at –2.892, 0.921, and 0.054 kcal/mol, respectively. Moreover, the quercetin showed binding energy of EGFR, K-ras oncogene protein, and TP53 at –1.249, –1.154, and –0.809 kcal/mol, respectively. The EGFR had the strongest bond with ellagic acid while K-ras oncogene protein and TP53 had the strongest interaction with quercetin. In order to identify the appropriate function, all these potential drug candidates can be further assessed through laboratory experiments.

      Keywords: EGFR, K-ras, TP53, curcumin, ellagic acid, quercetin, docking

1.1 Introduction

Lung cancer is known to be the number one cause of cancer deaths among all the cancer in both men and women in worldwide. According to a World Health Organization (WHO) survey, lung cancer caused 19.1 deaths per 100,000 in Malaysia, or 4,088 deaths per year (3.22% of all deaths) [1]. Moreover, there was a record of 1.69 million of deaths worldwide in 2015 due to lung cancer. Furthermore, a research in UK estimated that there will be 23.6 million of new cases of cancer worldwide each year by 2030 [1]. The main cause of lung cancer deaths is smoking. Almost 8% of people died because of it. Furthermore, the second reason is exposure to secondhand smoke. Thus, it is very clear that smoking is the leading risk factor for lung cancer. However, not everyone who got lung cancer is smokers as many people with lung cancer are former smokers while many others never smoked at all. Moreover, radiation exposure, unhealthy lifestyle, secondhand smoke, pollution of air, genetic markers, prolongs inhalation of asbestos, and chemicals as well as other factors can cause lung cancer non-smokers [2].

      Furthermore, it seems that most lung cancer signs do not appear until the cancer has spread, although some people with early lung cancer do have symptoms. Generally, the symptoms of lung cancer are a cough that does not go away and instead gets worse, shortness of breath, chest pain, feeling tired or weak, new onset of wheezing, and some lung cancer can even cause syndrome [3]. On top of that, a number of tests can be conducted in order to look for cancerous cell such as X-ray image of lung that could disclose the abnormal mass or nodule, a CT scan to exhibit small lesions in the lungs which may not detected on X-ray, blood investigations, sputum cytology, and tissue biopsy [4]. Lung cancer treatments being carried out are adjuvant therapy which may include radiation, chemotherapy, targeted therapy, or immunotherapy.

Since they originate from the bronchi within the lungs, small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC) are the two main clinic pathological classes for lung cancer. They are also known as bronchogenic carcinomas because they arise from the bronchi within the lungs [4]. Lung cancer is believed to be arising after a series of continuous pathological changes (preneoplastic lesions) which very often discovered accompanying lung cancers as well as in the respiratory mucosa of smokers. Apart from that, the genes involved in lung cancer are epidermal growth factor receptor (EGFR), KRAS, MET, LKBI, BREF, ALK, RET, and tumor suppressor gene (TP53) [5]. The three most common genes in lung cancer are EGFR, KRAS, and TP53, and the structure of these genes is explored in thus study. EGFR is actually transmembrane protein that has cytoplasmic kinase movement and it transduces essential development factor motioning from the extracellular milieu to the cell. According to da Cunha Santos, more than 60% of NSCLCs expresses EGFR which has turned into an essential focus for the treatment of these tumors [6]. In addition, the KRAS mutation is the most widely recognized oncogene driver change in patients with NSCLC and presents a poor guess in the metastatic setting, making it an imperative focus for tranquilize advancement. It is difficult to treat patients with KRAS mutations since there is no targeted therapy yet [7]. Among the mutations, the most common mutation that found to occur in lung cancer is TP53 mutations and its frequency becomes greater with tobacco consumption [8]. In this study, three compounds (curcumin, ellagic acid, and quercetin) were used for docking with the three mutant proteins. Curcumin has excellent safety profile that focus on different infections with solid confirmation on molecule level. Thus, improvement in formulation criteria can aid in developing therapeutic drug [9]. Next, ellagic acid has the ability to bind with cancer cells to make them inactive and it is also effective to resist cancer in rats and mice according to a research [10]. Quercetin is a pigment from plant (flavonoid) which has anti-oxidant and anti-inflammatory effect.